The secretion of adrenocorticotropin (ACTH) from the anterior pituitary gland in response to stress is under the stimulatory drive of several hypothalamic peptides, e.g., corticotropin-releasing factor (CRF) and arginine vasopressin (AVP). Other factors such as vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI) and serotonin (5-HT) also are thought to stimulate the secretion of ACTH. In contrast, the adrenal glucocorticoids exert a powerful negative feedback influence on ACTH secretion. The goal of these studies is to determine the physiological and pharmacological effects of VIP, PHI and 5-HT in controlling the secretion of ACTH in vivo. It is proposed to study the effect of exogenous VIP or PHI administration on the secretion of ACTH, CRF and AVP in vivo. Furthermore, utilizing passive immunization techniques, the role of endogenous VIP and/or PHI in stimulating ACTH secretion following adrenalectony or stress will be studied. Inasmuch as VIP and PHI appear to be hypothalamic hormones which are secreted into the hypophysial portal circulation, it is proposed to study the factors which regulate the secretion of these peptides into the portal blood and origin of these peptides in portal blood by collecting hypophysial portal blood from the anesthetized rat. Anatomical studies have demonstrated that VIP and 5-HT are present in overlapping loci in the suprachiasmatic and paraventricular nuclei and in the hippocampus. It is proposed to study the functional interrelationships between 5-HT and VIP in regulating ACTH secretion which involves these anatomical loci. Finally, it has been suggested that the hippocampus may mediate some of the negative feedback effects of the glucocorticoids. The importance of hippocampal VIP and 5-HT will be studied in mediating glucocorticoid negative feedback effects on ACTH secretion. These studies taken together will enhance our knowledge of the neurochemical interactions involved in the regulation of ACTH secretion. In man, hypercortisolemia is prevalent in patients suffering from depressive disorders and in the elderly. The etiology of the hypercortisolemia during depressive illnesses may involve changes in the metabolism of 5-HT or in the negative feedback signal produced by the glucocorticoids. The elderly may suffer hippocampal neuron loss which results in inappropriate feedback signals being relayed to the hypothalamic centers regulating ACTH secretion. Without more complete knowledge of the mechanisms governing ACTH secretion, there will be little hope of unraveling the mysteries of these idiopathic hypercortisolemic states.